GENES THAT PROMOTE ACAID AND INHIBIT OCULAR INFLAMMATION

眼免疫的独特性质的特征在于前房相关免疫偏离（ACAID），这是一种不寻常的免疫应答，其特征在于对前房中引入的抗原诱导的受抑制的DH。这种免疫应答本质上是全身性的。已知固有的眼部抗原呈递细胞在脾脏中诱导独特类型的抗原特异性调节细胞群，其被认为是ACAID中DH应答受抑制的原因。虽然已知眼部环境中的各种因素影响抗原呈递细胞以改变其功能，使得这些细胞获得诱导ACAID的能力，但是这些APC获得和表达这种独特能力的确切机制并不清楚。在眼环境中大量发现的细胞因子TGF β已被证明在APC的功能修饰中起重要作用，从而赋予它们诱导ACAID的能力。我们建议通过检查这些细胞内由TGF β在遗传水平诱导的变化来研究ACAID诱导的分子机制，这些变化反过来导致APC的功能改变。利用分子生物学技术的最新进展，我们已经成功地比较了传统的APCs与ACAID诱导的APCs的转录程序。应用差异显示分析（使用RAP-PCR），我们已经鉴定了由APC独特表达的基因，其在功能上类似于眼来源的APC。此外，我们最近采用DNA微阵列技术，以完成更全面的分析这些APC的表达谱。我们现在建议首先确定哪些差异表达的基因是合理的候选人ACAID诱导基于我们目前的知识的免疫反应在ACAID和现有的文献。然后，我们采用系统的方法，采用各种策略（如反义抑制，抗体或拮抗剂介导的抑制，使用某些基因选择性缺陷的转基因小鼠，化学或药理学诱导）。试剂或基因转染）来研究所选候选基因与ACAID的功能相关性。这种方法来检查参与特定的基因产物赋予独特的功能能力的眼睛来源的APC不仅会提高我们的理解仔细调节眼部免疫反应，但引起建议的治疗，通过该治疗可以选择性地操纵眼部微环境。

The unique nature of ocular immunity is characterized by anterior chamber associated immune deviation (ACAID), an unusual immune response that is eye characterized by suppressed DH induced to antigens introduced in the anterior chamber. Such an immune response is systemic in nature. Indigenous ocular antigen presenting cells are known to induce a unique type of antigen-specific regulatory cell population in the spleen which is believed to be responsible for suppressed DH responses in ACAID. While it is known that various factors in the ocular environment influence antigen presenting cells to modify their function such that these cells acquire the ability to induce ACAID, the exact mechanisms by which these APCs acquire and express this unique ability is not dearly understood. A cytokine found in abundance in the ocular environment, TGFP, has been demonstrated to play a significant role in functional modification of APCs thereby conferring upon them the ability to induce ACAID. We propose to study molecular mechanisms underlying ACAID induction by examining changes induced within these cells at genetic levels, by TGF[3, changes which in turn lead to functional alterations of an APC. Taking advantage of the latest advances in molecular biology techniques we have successfully compared the transcriptional program of conventional APCs with that of ACAID-inducing APCs. Applying differential display analysis (using RAP-PCR) we have identified genes uniquely expressed by the APCs that functionally resemble eye- derived APCs. Furthermore, we have recently employed DNA microarray technology to accomplish a more comprehensive analysis of expression profiles of these APCs. We now propose to first determine which of the differentially expresssed genes are reasonable candidates for ACAID induction based on our current knowledge of the immune response in ACAID and the available literature. We then adopt a systematic approach, employing various strategies (such as antisense inhibition, antibody or antagonist mediated inhibition, use of transgenic mice selectively deficient in certain genes, induction by chemical or pharmacological . agents or gene transfection) to study the functional relevance to ACAID of the selected candidate genes. Such an approach to examine involvement of specific gene products in conferring unique functional capabilities on eye-derived APCs will not only enhance our understanding of carefully regulated ocular immune responses but give rise to suggested therapies by which the ocular microenvironment can be selectively manipulated.